Inga Marie Nilsson

Twenty-five years' experience of prophylactic treatment in severe haemophilia A and B.

In Sweden, prophylactic treatment of boys with severe haemophilia has been practised since 1958 in an attempt to convert the disease from a severe to a milder form. The present study population consisted of 60 severe haemophiliacs (52 A, 8 B), aged 3–32 years. Treatment is started when the boys are 1–2 years of age, the regimens used being 24–40 IU F VIII kg−1 three times weekly in haemophilia‐A cases (i.e. > 2000 IU kg−1 annually) and 25–40 IU F IX kg−1 twice weekly in haemophilia‐B cases. The orthopaedic and radiological joint scores (maximum scores of 90 and 78, respectively) are evaluated as recommended by the World Federation of Haemophilia. Of those subjects aged 3–17 years, 29 out of 35 individuals had joint scores of zero. The oldest group had only minor joint defects. The VIII:C and IX:C concentrations had usually not fallen below 1% of normal. All 60 patients are able to lead normal lives. In conclusion, it appears to be possible to prevent haemophilic arthropathy by giving effective continuous prophylaxis from an early age, and preventing the VIII:C or IX:C concentration from falling below 1% of normal.

Haemophilia prophylaxis in young patients--a long-term follow-up.

Objectives. To review long‐term prophylactic factor treatment in young patients with severe haemophilia A and B, focusing on the orthopaedic and radiological outcome.

Induction of Immune Tolerance in Patients with Hemophilia and Antibodies to Factor VIII by Combined Treatment with Intravenous IgG, Cyclophosphamide, and Factor VIII

The development of antibodies to factor VIII is a serious complication of the treatment of patients with hemophilia A. We successfully induced immune tolerance in patients with such antibodies with a new treatment protocol, which combined factor VIII, cyclophosphamide, and high-dose intravenous IgG, followed by regular prophylactic treatment with factor VIII. This protocol has now been used in 11 patients with hemophilia A, of whom 9 had a strong antibody response. When the initial concentration of antibodies exceeded 3 Malmö inhibitor units (corresponding to about 10 Bethesda units) per milliliter, treatment was preceded by adsorption of antibody to protein A. After two to three weeks of the combined treatment, factor VIII coagulant antibodies had disappeared in 9 of the 11 patients; in 8 of these 9 patients the half-life of infused factor VIII had normalized. The tolerant state appears to be stable after a median of 30 months. Two patients did not respond to the treatment. Because earlier treatment with factor VIII and cyclophosphamide or with factor VIII and IgG had been ineffective in these patients, our experience suggests that all three components of the protocol are required for the successful induction of tolerance to factor VIII.

Platelet Aggregation Induced by I-Desamino-8-D-Arginine Vasopressin (dDAVP) in Type IIb von Willebrand's Disease

Type IIB von Willebrands disease is a distinct form of this disorder, in which there are abnormal factor VIII/von Willebrand factor multimers in plasma (but normal multimers in platelets) and heightened interaction between the von Willebrand factor and platelets in the presence of ristocetin. We have found that infusion of desmopressin acetate (1-desamino-8-D-arginine vasopressin [DDAVP]), an agent used in the treatment of von Willebrands disease, causes platelet aggregation and thrombocytopenia in patients with Type IIB disease. In vitro, platelets in normal plasma and those obtained from patients with Type IIB disease before DDAVP infusion aggregated upon the addition of platelet-poor plasma from Type IIB patients treated with DDAVP. Platelet aggregation was associated with adsorption of multimers of factor VIII/von Willebrand factor onto the platelets and was inhibited by EDTA. We conclude that in Type IIB von Willebrands disease, DDAVP releases an abnormal factor with platelet-aggregating properties. DDAVP should not be used to treat patients with Type IIB disease, since the presence of platelet aggregates in the circulation may be harmful.

Clinical pharmacology of aminocaproic and tranexamic acids

In a systematic search for a substance with antifibrinolytic properties Okamoto and his group in Japan found that several mercaptoand aminocarbonic acids were active. Of these substances epsilon-aminocaproic acid (EACA) had the strongest antifibrinolytic effect.1 2 The Japanese workers described it as a plasmin inhibitor in vitro and useful in inhibiting proteolytic enzymes in vivo. They gave EACA in a dose of 10-20 g a day by mouth or intravenously to over 100 patients and observed no toxic effects. Their investigation did not include any metabolic studies. EACA has since been widely used and its mode of action and pharmacokinetics intensively studied. In a continued search for more potent antifibrinolytic components p-aminomethyl cyclohexane ,arboxylic acid (AMCHA) was found to be more potent than EACA.3 This compound contains two stereoisomers. Independently Melander et al.4 and Okamoto et al.5 found that only the trans-form was antifibrinolytically active. The antifibrinolytically active form was called tranexamic acid (AMCA). It is 6-10 times stronger than EACA and is now used more widely. Its pharmacokinetics have been the subject of several studies. This paper surveys the pharmacology and toxicology ofEACA and AMCA.

HAEMOPHILIA PROPHYLAXIS IN SWEDEN

ABSTRACT. 29 boys (4–18 years old) with severe haemophilia A were given prophylactic infusions of AHF concentrate (human fraction I–0) for 2 to 13 years in an attempt to change the haemophilia from a severe to a moderate form and thereby prevent arthropathy and severe bleeding episodes. The sizes of the doses and the intervals at which the doses were given were titrated by AHF survival studies. As a rule, the patients received AHF in amounts sufficient to raise the AHF level to 30–45% at 5–12 day intervals. In about 50% of the infusions the AHF content was not below 1% before the next infusion. During such prophylaxis all patients except one have been in a good general condition. They have had bleeding episodes, which have, however, been much less severe and less frequent. The children have been able to live an almost normal life. The number and duration of stays in hospital have been markedly reduced. 17 of the patients had only minor or no joint defects before the start of the treatment. In this group the joint function was identical with that found in moderate haemophilia in the same age groups. Two patients developed anticoagulants. No other side effects were seen.

Genetic variants of von Willebrand's disease.

A specific antiserum against an antihaemophilic factor (AHF)-related plasma protein was raised in rabbits. A quantitative immunochemical method was used to determine the amount of this protein present in the plasma of 33 patients with haemophilia A and 70 patients with von Willebrands disease. The protein probably consisted of AHF residing in or complexed with the von Willebrand factor. The patients with von Willebrands disease were shown to fall into two separate genetic groups, one with decreased and one with normal amounts of the AHF-related protein. The patients with haemophilia A had normal amounts of the protein in their plasma.

Aberrant multimeric structure of von Willebrand factor in a new variant of von Willebrand's disease (type IIC).

A variant of von Willebrands disease has been identified in which sodium dodecyl sulfate agarose electrophoresis provides evidence that the von Willebrand factor present is structurally abnormal. Rather than the repeating triplet seen in normal subjects and in patients with the IIA and IIB variants, a repeating doublet was present in the propositus. None of the bands had the same mobility as bands in normal subjects or previously described von Willebrands disease patients. The larger multimers of von Willebrand factor were lacking both from plasma and platelets, and did not appear in the circulation after infusion of 1-deamino-[8-D-arginine]-vasopressin. There was a marked increase in the concentration of the smallest multimer in the propositus and his phenotypically normal children, indicating that this abnormality of von Willebrand factor is inherited in an autosomal-recessive manner.

FIBRINOLYTIC ACTIVITY OF HUMAN VEINS

Abstract Arm veins have a higher fibrinolytic activity than leg veins as determined histochemically. Blood fibrinolysis stimulated by stasis is higher in the arms than in the legs. In patients with thrombosis, vein and blood fibrinolytic activity are lower, especially in the legs.

Antithrombin III in a clinical material

Abstract Antithrombin III (AT III) has been determined in 368 patients including 192 with recurrent deep venous thrombosis, 17 women with thrombosis during contraceptives, 28 women on oral contraceptives, 10 patients with myocardial infarction, 49 with renal diseases, 59 with different types of cancer and 13 with liver cirrhosis. In addition 25 patients were examined pre- and post-operatively. Both a biological method (5) and an immunochemical method were used. In addition albumin, orosomucoid, haptoglobin and immunoglobulin were assayed immunochemically. Normal range (40 healthy persons) was found to be 75–122 % with both methods and no sex differences were seen. All but two of the patients with recurrent deep vein thrombosis or myocardial infarction had normal or elevated values of AT III with both methods. All women with thrombosis during treatment with contraceptives and those examined during such treatment had normal or elevated levels. The same pattern was found among the patients with cancer and renal diseases. All patients with liver cirrhosis had decreased levels of AT III. No significant postoperative decrease of AT III was observed. A positive correlation between AT III and albumin or haptoglobin was found which indicates that the AT III reacts as an acute phase reactant.